Self-augmentation of the lengthening of repolarization is related to the shape of the cardiac action potential: Implications for reverse rate dependency

BACKGROUND AND PURPOSE: The aims of the present work were to study the mechanism of the reverse rate dependency of different interventions prolonging cardiac action potential duration (APD). EXPERIMENTAL APPROACH: The reverse rate-dependent lengthening effect of APD-prolonging interventions and the possible involvement of I(Kr) (rapid component of the delayed rectifier potassium current) and I(K1) (inward rectifier potassium current) were studied by using the standard microelectrode and the whole-cell patch-clamp techniques in dog multicellular ventricular preparations and in myocytes isolated from undiseased human and dog hearts. KEY RESULTS: All applied drugs--dofetilide (1 micromol.L(-1)), BaCl(2) (10 micromol.L(-1)), BAY-K-8644 (1 micromol.L(-1)), veratrine (1 microg.mL(-1))--lengthened APD in a reverse rate-dependent manner regardless of their mode of action, suggesting that reverse rate dependency may not represent a specific mechanism of APD prolongation. The E-4031-sensitive current (I(Kr)) and the Ba(2+)-sensitive current (I(K1)) were recorded during repolarizing voltage ramps having various steepness and also during action potential waveforms with progressively prolonged APD. Gradually delaying repolarization results in smaller magnitude of I(Kr) and I(K1) currents at an isochronal phase of the pulses. This represents a positive feedback mechanism, which appears to contribute to the reverse rate-dependent prolongation of action potentials. CONCLUSIONS AND IMPLICATIONS: Action potential configuration may influence the reverse rate-dependent APD prolongation due to the intrinsic properties of I(Kr) and I(K1) currents. Drugs lengthening repolarization by decreasing repolarizing outward, or increasing depolarizing inward, currents are expected to cause reverse rate-dependent APD lengthening with high probability, regardless of which current they modify.